The vast majority of cancers arising in the oral cavity are squamous cell carcinomas. The Keratinocyte Biology Group was established in January, 1998 to elucidate mechanisms of squamous cell differentiation and the biochemical alterations contributing to the neoplastic phenotype and malignant conversion. Our work has utilized keratinocytes of murine epidermis and both in vitro and in vivo approaches to dissect the stages of differentiation and neoplastic progression. The p53 tumor suppressor gene is mutated or inactivated in a majority of human cancers, including those of the oral cavity, and our studies have focused on elucidating the function and mechanism of action of this gene product in keratinocyte biology. The cyclin dependent kinase inhibitor WAF1, a downstream target of p53 mediated gene transcription, is believed to be an effector of tumor suppression by p53. We have explored the role of the WAF1 gene product in multistep carcinogenesis, and using both in vivo and in vitro models have demonstrated that loss of WAF1 is not sufficient to explain the malignant phenotype of p53 null tumors; thus, other features of p53 beside transcriptional activation of the WAF1 gene are necessary for its tumor suppressor function. In addition, by differential display analysis we have identified a novel p53 regulated gene that is also part of the TNF-alpha pathway and have found that this overexpression of this gene product rapidly induces keratinocyte cell death. Because the p53 protein is inactivated in a majority of cancers arising in the oral cavity, elucidating this pathway should help to clarify the etiology of oral carcinogenesis and suggest novel therapeutic interventions. - keratinocyte, squamous differentiation, epidermal carcinogenesis, tumor suppression